Morgan Daniel L, Merrick B Alex, Gerrish Kevin E, Stockton Patricia S, Wang Yu, Foley Julie F, Gwinn William M, Kelly Francine L, Palmer Scott M, Ton Thai-Vu T, Flake Gordon P
Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America.
Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America.
PLoS One. 2015 Feb 24;10(2):e0118459. doi: 10.1371/journal.pone.0118459. eCollection 2015.
Obliterative bronchiolitis (OB) is an irreversible lung disease characterized by progressive fibrosis in the small airways with eventual occlusion of the airway lumens. OB is most commonly associated with lung transplant rejection; however, OB has also been diagnosed in workers exposed to artificial butter flavoring (ABF) vapors. Research has been limited by the lack of an adequate animal model of OB, and as a result the mechanism(s) is unclear and there are no effective treatments for this condition. Exposure of rats to the ABF component, 2,3-pentanedione (PD) results in airway lesions that are histopathologically similar to those in human OB. We used this animal model to evaluate changes in gene expression in the distal bronchi of rats with PD-induced OB. Male Wistar Han rats were exposed to 200 ppm PD or air 6 h/d, 5 d/wk for 2-wks. Bronchial tissues were laser microdissected from serial sections of frozen lung. In exposed lungs, both fibrotic and non-fibrotic airways were collected. Following RNA extraction and microarray analysis, differential gene expression was evaluated. In non-fibrotic bronchi of exposed rats, 4683 genes were significantly altered relative to air-exposed controls with notable down-regulation of many inflammatory cytokines and chemokines. In contrast, in fibrotic bronchi, 3807 genes were significantly altered with a majority of genes being up-regulated in affected pathways. Tgf-β2 and downstream genes implicated in fibrosis were significantly up-regulated in fibrotic lesions. Genes for collagens and extracellular matrix proteins were highly up-regulated. In addition, expression of genes for peptidases and peptidase inhibitors were significantly altered, indicative of the tissue remodeling that occurs during airway fibrosis. Our data provide new insights into the molecular mechanisms of OB. This new information is of potential significance with regard to future therapeutic targets for treatment.
闭塞性细支气管炎（OB）是一种不可逆的肺部疾病，其特征是小气道进行性纤维化，最终导致气道管腔闭塞。OB最常与肺移植排斥反应相关；然而，在接触人造黄油香料（ABF）蒸气的工人中也诊断出了OB。由于缺乏合适的OB动物模型，相关研究受到限制，因此其发病机制尚不清楚，且尚无有效的治疗方法。将大鼠暴露于ABF成分2,3 - 戊二酮（PD）会导致气道病变，其组织病理学特征与人类OB相似。我们利用这个动物模型来评估PD诱导的OB大鼠远端支气管中基因表达的变化。雄性Wistar Han大鼠每天暴露于200 ppm的PD或空气中6小时，每周5天，持续2周。从冷冻肺的连续切片中激光显微切割支气管组织。在暴露的肺中，收集纤维化和非纤维化气道。经过RNA提取和微阵列分析后，评估差异基因表达。在暴露大鼠的非纤维化支气管中，相对于空气暴露对照组，有4683个基因发生了显著改变，许多炎性细胞因子和趋化因子明显下调。相比之下，在纤维化支气管中，有3807个基因发生了显著改变，受影响通路中的大多数基因上调。在纤维化病变中，Tgf-β2及其下游与纤维化相关的基因显著上调。胶原蛋白和细胞外基质蛋白的基因高度上调。此外，肽酶和肽酶抑制剂的基因表达也发生了显著改变，表明气道纤维化过程中发生了组织重塑。我们的数据为OB的分子机制提供了新的见解。这些新信息对于未来的治疗靶点具有潜在意义。
